Aiming to understand the origin of CD8+ T cell responses against adeno-associated viral (AAV) gene therapy vectors, Shirley et al. investigated the requirements for effective cross-priming. Inhibition of type 1 IFN receptor (IFNAR) with antibody or deletion of IFNAR1 in cDCs prevented capsid-specific CD8+ T cell activation, but did not affect AAV capsid antigen presentation by cDCs. Anti-capsid CD8+ T cell activation was independent of NK cells. In addition to the inflammatory stimulus, cDC-mediated priming of CD8+ T cells required CD40-CD40L interaction with CD4+ T helper cells.
Contributed by Shishir Pant
ABSTRACT: Adeno-associated virus (AAV) vectors are widely used in clinical gene therapy to correct genetic disease by in vivo gene transfer. Although the vectors are useful, in part because of their limited immunogenicity, immune responses directed at vector components have complicated applications in humans. These include, for instance, innate immune sensing of vector components by plasmacytoid dendritic cells (pDCs), which sense the vector DNA genome via Toll-like receptor 9. Adaptive immune responses employ antigen presentation by conventional dendritic cells (cDCs), which leads to cross-priming of capsid-specific CD8(+) T cells. In this study, we sought to determine the mechanisms that promote licensing of cDCs, which is requisite for CD8(+) T cell activation. Blockage of type 1 interferon (T1 IFN) signaling by monoclonal antibody therapy prevented cross-priming. Furthermore, experiments in cell-type-restricted knockout mice showed a specific requirement for the receptor for T1 IFN (IFNaR) in cDCs. In contrast, natural killer (NK) cells are not needed, indicating a direct rather than indirect effect of T1 IFN on cDCs. In addition, co-stimulation by CD4(+) T cells via CD40-CD40L was required for cross-priming, and blockage of co-stimulation but not of T1 IFN additionally reduced antibody formation against capsid. These mechanistic insights inform the development of targeted immune interventions.
Author Info: (1) Department Pediatrics, University of Florida, Gainesville, FL, USA. (2) Department Pediatrics, University of Florida, Gainesville, FL, USA. (3) Department Pediatrics, Universit
Author Info: (1) Department Pediatrics, University of Florida, Gainesville, FL, USA. (2) Department Pediatrics, University of Florida, Gainesville, FL, USA. (3) Department Pediatrics, University of Florida, Gainesville, FL, USA. (4) Department Pediatrics, University of Florida, Gainesville, FL, USA. (5) Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. (6) Department Pediatrics, University of Florida, Gainesville, FL, USA. (7) Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA. (8) Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA. (9) Division of Immunology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA, USA. (10) Department Pediatrics, University of Florida, Gainesville, FL, USA; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: rwherzog@iu.edu.
